NMR structure of a potent small molecule inhibitor bound to human keratinocyte fatty acid-binding protein

  • J Med Chem. 2006 Aug 10;49(16):5013-7. doi: 10.1021/jm060360i.
Patricia A McDonnell  1 ,  Keith L Constantine ,  Valentina Goldfarb ,  Stephen R Johnson ,  Richard Sulsky ,  David R Magnin ,  Jeffrey A Robl ,  Thomas J Caulfield ,  Rex A Parker ,  David S Taylor ,  Leonard P Adam ,  William J Metzler ,  Luciano Mueller ,  Bennett T Farmer 2nd
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA. [email protected]
PMID: 16884313 DOI: 10.1021/jm060360i
Abstract

The NMR structure is presented for compound 1 (BMS-480404) (Ki = 33 (+/-2) nM) bound to keratinocyte fatty acid-binding protein. This article describes interactions between a high affinity drug-like compound and a member of the fatty acid-binding protein family. A benzyl group ortho to the mandelic acid in 1 occupies an area of the protein that fatty acids do not normally contact. Similar to that in the kFABP-palmitic acid structure, the acid moiety in 1 is proximal to R129 and Y131. Computational modeling indicates that the acid moiety in 1 interacts indirectly via a modeled water molecule to R109.

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